There is now strong evidence that FSGS is caused by podocyte depletion due to accelerated podocyte loss from glomeruli. We have shown that relative podocyte depletion can also occur if glomeruli enlarge without actually reducing the number of podocytes. Podocytes have limited capacity to divide and be replaced and therefore depend on hypertrophy to compensate for increased glomerular size during normal growth of childhood and especially in association with excessive glomerular growth such as occurs in association with obesity and diabetes. The hypothesis to be tested is that FSGS and progression to ESKD can be initiated and driven by failure of podocytes to respond adequately to hypertrophic stress during increased glomerular growth. To test this hypothesis we developed a new podocin-AA-4EBP1 transgenic rat model designed to specifically limit podocyte enlargement with the expectation (proven to be correct by preliminary data) that podocyte- specific expression of the transgene will predispose to development of FSGS during normal growth. We will use the model to test the hypothesis that growth itself can trigger the FSGS pathways to progression in susceptible individuals through the mTOR pathway. We will determine whether FSGS and progression in this model can be accelerated by factors that increase kidney growth such as uninephrectomy (as commonly occurs during transplant donation or nephrectomy for carcinoma of the kidney), or by insulin and growth factor treatments. We will determine whether FSGS and progression can be prevented by drugs in common use that will prevent glomerular growth such as calorie restriction, rapalogues and metformin. We will also test the hypothesis that angiotensin2 blockade will not prevent glomerular enlargement or the initial FSGS lesions, but will prevent accelerated glomerulosclerosis. If these hypotheses are correct then relatively simple steps, which are within current therapeutic capability, could significantly retard or prevent development of FSGS, glomerulosclerosis and progression to ESKD. The nation is facing an epidemic of overweight, obesity and type 2 diabetes (with parallel glomerular enlargement) affecting both adults and children with particular impact on minority groups. The focus of this application is therefore both timely and important as we strive to reduce the prevalence of ESKD currently costing >$50 billion annually with high mortality and morbidity for patients and their families.